A variety of chromosomal aberrations have been associated with the occurrence of B cell and T cell cancers in humans and animals. Among such chromosomal abnormalities are deletions or inversions of all or a portion of certain gene sequences. Additionally, translocations of certain genes or fragments of genes from part of one chromosome to another chromosome or to a different part of the same chromosome have also been observed in various forms of cancer. Specific chromosomal translocations observed in human and animal tumors are thus believed to play a role in tumorigenesis.
The breakpoint of a chromosome rearrangement is that region at which the covalent bonds between nucleotides comprising the DNA backbone of one chromosome break and reform at a new position with other nucleotides in the same chromosome after a chromosomal deletion or with nucleotides derived from a different chromosome in a chromosomal translocation. The resulting chromosome may be a shorter version of the original chromosome due to a deletion or a hybrid chromosome formed by the joining between the original chromosome or a portion thereof with a portion of a different chromosome.
In many translocations the breakpoints lie near the loci of certain transforming genes. These observations have suggested that tumor development is partly due to the activation of these genes which normally perform the function of regulating cellular growth. In some cases a chromosomal abnormality may disable a suppressor gene which normally functions to repress cell proliferation. The transforming genes near the breakpoint or the point of disablement of the suppressor gene may thus initiate the unrepressed cellular development characteristic of tumor formation.
More specifically chromosome 11 has been identified as the site of a number of chromosomal abnormalities which have been observed and are correlated with the occurrence of certain human cancers. I. U. Ali et al, Science, 238:185-188 (1987) report a loss of heterozygocity for multiple loci on chromosome 11 which are correlated with the occurrence of certain aggressive breast tumors. Specifically, hybridization signals of most of the cases studied by Ali et al which were heterozygous for markers on the short arm of chromosome 11, were consistent with deletion of sequences on the short arm. Thus, the frequency of deletions on 11p in breast carcinomas was concluded to support the existence of regulatory sequences important in the genesis of breast tumors. Although about one in ten women develops breast cancer, presently, such aggressive breast carcinoma is not specifically detectable in its early stages from other less aggressive forms of breast cancer. Sequences on the short arm of chromosome 11 are implicated in the suppression of tumorigenicity of breast cancer derived Hela cells breast cancer derived cells [H. Klinger, Cytogenet. Cell Genet., 32:68 (1982); E. J. Stanbridge, Bioassays, 3:252 (1985).]
In addition to its correlation with breast cancer, deletions and/or translocations on the short arm of chromosome 11 have also been associated with the occurrence of Wilms tumor, hepatoblastoma, hepatocellular carcinoma, and transitional cell carcinoma of bladder. Abnormalities at the 11p13 region have also been shown to be associated with embryonal carcinoma [A. Kaufos et al, Nature, 316:330-334 (1985)].
Wilms' tumor, aniridia, genito-urinary abnormalities and mental retardation collectively are referred to as WAGR. [See, S. H. Orkin et al, Nature. 309:172-174 (1984); and E. R. Fearon et al, Nature, 309:176-178 (1984)].
Wilms' disease is believed to be a hereditary disease which occurs in one out of every 50,000 newborns. This disease has also been observed to occur sporadically, i.e. without a hereditary basis, in five out of every 50,000 newborns. A recent report, Lewis et al, Genomics, 3:25-31 (1988) has shown that the breakpoint between chromosomes 11 and 14 in a patient having T cell acute lymphocytic leukemia (T-ALL) is closely linked to the locus for the WAGR.
Mapping studies have indicated the relative placement of certain translocation breakpoints on chromosome 11. L. C. Showe and C. Croce, Ann. Rev. Imm 5:253-277 (1987) review a particular region p13 on chromosome 11 which has been suggested to harbor a new oncogene or anti-oncogene which potentially plays an important role in the development of T cell leukemias. This report localizes that sequence to approximately the 5' portion of a breakpoint between chromosomes 11 and 14.
T. Boehm et al EMBO J., 7(7):2011-2017 (1988) disclose the detection of an 800 base pair region derived from chromosome 11p13 which contains a cluster of breakpoint sequences presumably involved in the pathogenesis of T-ALL. This report discloses a 0.65 kilobase region covered by the probe and provide a nucleotide sequence thereof.
There is a need in the art for agents for both diagnostic and therapeutic use which are capable of detecting and differentiating between different forms of breast cancer and other cancers and diseases associated with genetic abnormalities. Such diagnostic agents and tests would enable the selection of different types of presently available therapies for the condition so identified, and may also provide novel avenues of therapy.